Page 75 - Read Online

Page 274 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

Table 1. Epigenetically modifiable promoter genes relevant to ovarian cancer
Promoter genes
DNA methylation APC, ESR, MGMT, RASSF1A, MLH1, TERT, WT1
Testis/ovarian cells BORIS/CTCFL, DAX1, FOXL2, RSPO1, TMEFF2
Wnt pathway APC, DKK1, DKK2, DKK3, SFRP1, SFRP4, SFRP5, WIF1, WNT4
DNA repair pathways BRCA1, MGMT, MLH1
APC: adenomatous polyposis coli; BORIS/CTCFL: brother of the regulator of imprinted sites/CCCTC-binding factor like; BRCA1:
breast cancer 1; DAX1: dosage-sensitive sex reversal-adrenal hypoplasia congenital critical region on the X chromosome gene 1; DKK:
dickkopf; ESR: estrogen receptor; FOXL2: forkhead box L2; MGMT: O-6-methylguanine-DNA methyltransferase; MLH1: mutL homolog 1;
RASSF1A: ras association domain family member 1; RSPO1: R-spondin 1; SFRP: secreted frizzled-related protein; TERT: telomerase reverse
transcriptase; TMEFF2: transmembrane protein with EGF like and two follistatin like domains 2; WIF1: WNT inhibitory factor 1; WNT4:
Wnt family member 4; WT1: Wilms tumor 1

Table 2. Epigenetically modifiable genes relevant to ovarian cancer resistance and sensitization to cisplatin/carboplatin
Resistance/sensitization Genes
[19]
Cisplatin resistance OXCT1 [18] , GPCR , TET1 [20] , MLH1 [21-23] , HOXA10, HOXA11 [21,24] , NAGA [25] , UCHL1 [26] ,
BCL2L1 [27] , FANCF [28-30]
Cisplatin sensitization FANCF [31] , NAGA [25] , CCDC69 [32] , UCHL1 [26]
[40]
[37]
Carboplatin Resistance TMEM88 [33] , DOK2 [34,35] , p57(Kip2) [36] , Plk2 , HERV-K [38] , SFRP5 [39] , SLFN11 , ASS1 [41]
ASS1: argininosuccinate synthase 1; BCL2L1: BCL2 like 1; CCDC69: coiled-coil domain containing 69; DOK2: docking protein 2; FANCF:
fanconi anemia complementation group F; GPCR: protein coupled receptor; HOXA: homeobox A cluster; HERV-K: for HERV-K: human
endogenous retrovirus type K; MLH1: mutL homolog 1; NAGA: N-acetylgalactosaminidase; OXCT1: 3-oxoacid CoA-transferase 1; Plk2:
polo like kinase 2; SFRP5: secreted frizzled-related protein 5; SLFN11: schlafen family member 11; TET1: tet methylcytosine dioxygenase 1;
TMEM88: transmembrane protein 88; UCHL1: ubiquitin C-terminal hydrolase L1

topics, such as ovarian cancer.

Using the various methods available, a number of abnormal DNA methylation patterns have been
demonstrated in cancer cells with specific consequences being identified . Hence, global hypomethylation
[46]
can lead to chromosomal and genetic instability as well as reactivation of endoparasitic and repetitive
genomic sequences. In addition, hypomethylation of gene bodies can activate incorrect sites of transcription
initiation while the loss of promoter methylation can cause activation of metastasis and tumor promoting
genes.

EPITHELIAL-MESENCHYMAL TRANSITION
Epithelial-mesenchymal transition (EMT) is a hallmark of cancer progression and metastasis. During this
process, epithelial cells go through phenotypic changes and acquire mesenchymal characteristics. They lose
their cell polarity and cell-cell adhesion and acquire migratory and invasive properties, facilitating their
migration through the extracellular matrix and settlement in other organs. This molecular reprogramming
and cell switch lead to the loss of cytokeratins and epithelial-specific junction proteins, e.g., E-cadherin,
mediated by upregulation of the transcriptional repressors Snail and Slug, ZEB1 and ZEB2, and Twist,
and turning on the expression of mesenchymal markers e.g. Vimentin and N-cadherin. EMT is induced
by a variety of signals, including the Wnt/β-catenin signaling pathway, Notch transcription factors,
phosphoinositide-3 kinase (PI 3K)/Akt signaling .
[47]

SIGNALLING PATHWAYS
The following paragraphs contain a short overview on the signaling pathways most frequently involved in
platinum resistance.

Wnt signaling
The Wnt signaling pathway is a complex developmental cell signaling pathway which plays an essential
role in embryogenesis. The network is generally divided into the β-catenin dependent (canonical) and the